Treatment of ulcers of the gastrointestinal tract using dimethylpolysiloxane

ABSTRACT

Dimethylpolysiloxane is effective in the treatment of ulcers of the gastrointestinal tract.

DESCRIPTION

The invention is in the area of the drug treatment of ulcerous disorders of the gastrointestinal tract.

The defoaming effect of dimethylpolysiloxane is well investigated and is already used therapeutically as antiflatulent or in preparation for sonography.

It has been found, surprisingly, that dimethylpolysiloxane can be employed with a particularly advantageous effect for the treatment of ulcerous disorders of the gastrointestinal tract. The defoaming effect of dimethylpolysiloxane is correlated with the other physicochemical properties film-formation and adhesion to walls. It has emerged, surprisingly, that dimethylpolysiloxane can also be administered orally over extended periods without disadvantageous effects in order to form and maintain in the oesophagus and in the gastrointestinal tract of humans a protective layer which assists the healing process when disorders of the type described are present.

The agent according to the invention is particularly employed for the treatment of ulcerous disorders of the qastrointestinal tract, generally of disorders of the oesophagus, of the stomach and upper small intestine, such as oesophagitis, ulcers (gastric and duodenal).

It is used in the form of an orally administerable composition with a pharmaceutically acceptable diluent or carrier, e.g. in the form of chewable tablets.

The use according to the invention of dimethylpolysiloxane experiences an increase in its effectiveness when the agent is taken in conjunction with silica gel.

This results in the coating which is generated by the agent in the oesophagus and gastrointestinal tract having a gel-like structure. This layer comes very close to the physiological mucus (e.g. gastric mucus) which protects the mucous membranes of the oesophagus and gastrointestinal tract.

It is possible with the agent employed according to the invention specifically to coat the mucous membranes of oesophagus and gastrointestinal tract over a prolonged period by appropriate intake even for days, weeks or months, and thus protect them against the aggressive constituents of the gastrointestinal tract, such as hydrochloric acid and digestive enzymes. The protection brought about by the agent employed according to the invention effects, on the one hand, a reduction in the activity of tissue-damaging mechanisms and, on the other hand, a comparatively unimpaired regeneration of the walls associated with the cell regeneration and with the ulcer cleansing. The agent employed according to the invention additionally brings about an increase in the pH (buffering of raised acid values) in the stomach. The subjective feeling of the patient improves due to intake of the agent, the `heartburn`, of the frequently hyperacid patients disappears.

INVESTIGATIONS

The following were investigated as a function of the dose and time:

1. Distribution and film-formation of dimethylpolysiloxane in the stomach.

2. Distribution and film-formation of dimethylpolysiloxane in the duodenum.

8 healthy men aged 25 and 40 years were employed as volunteer subjects (Table 1). The study was carried out as a controlled, randomized phase I study in crossover design. For the crossover design, the 8 subjects were randomized and assigned to the two dosage forms. The investigations were carried out at an interval of 7 days.

Two dosages were used per subject in the crossover design:

Dosage 1: 80 mg of dimethylpolysiloxane: (2×40 mg dimethylpolysiloxane chewable tablets)

Dosage 2: 160 mg of dimethylpolysiloxane: (4×40 mg dimethylpolysiloxane chewable tablets)

The composition of the dimethylpolysiloxane chewable tablets is shown in Table 8.

No other drugs were allowed to be taken immediately before and during the study. Furthermore, smoking was not permitted on the day of the investigation.

CONTROL INVESTIGATIONS

A comprehensive history was taken at the initial investigation; in addition the basic physical and neurological investigations. Laboratory tests were also carried out.

The following gastroenterological progress investigations were carried out on all the subjects on both investigation days:

1. Gastroscopy with documentation of oesophagus, stomach and duodenum immediately before chewing the dimethylpolysiloxane tablets.

2. The same investigations, including the documentation, 30 minutes after taking the chewable tablets.

3. The same investigations, including the documentation, 2 hours after chewing the dimethylpolysiloxane chewable tablets.

The investigations were carried out twice for each subject, with each alternative dosage, at an interval of 7 days. At a second progress investigation, in addition the pH of the stomach contents was measured at each gastroscopy.

The subjects were not allowed to take any food or drink for at least 6 hours before each drug intake and gastroscopy.

To prepare for the endoscopy, each subject received 0.5 mg of atropine in 1 ml of NACL solution administered subcutaneously. The local anaesthetic given for the mouth and pharyngeal space was Wander Novescine 1% solution (oxybuprocaine-HCL).

The gastroscopic investigations were carried out with an Olympus type P₁₀ instrument. Documentation was effected by the visual findings and photography.

RESULTS

1. Change in the stomach pH

Table 2 summarizes the changes in pH based on the pH at the investigation immediately before medication and 2 hours after medication.

The dimethylpolysiloxane administration leads to a distinct increase in the pH, i.e. a distinct shift from strongly acid in the direction of the alkaline range, irrespective of the number of chewable tablets administered. Despite the small number of subjects, this difference is significant at the 5% level.

Subject 7 was removed from the calculation because he had a duodenal cap greatly deformed by scarring and, moreover, the pH was already near the alkaline range (pH 6.05 or 6.83).

2. Film formation

Table 3 summarizes the individual results in Tables 4 to 7. The aim of the study was to demonstrate that the dimethylpolysiloxane remained in the stomach or duodenum in the observed period of 2 hours after administration of chewable tablets. The results are unambiguous. Administration of only 2 tablets of dimethylpolysiloxane (80 mg) leads to a reaction in all the subjects. This is even more evident due to administration of 4 tablets of dimethylpolysiloxane (160 mg).

At 360 mg, a relatively large amount of milky secretion was evident as observation parameter on the gastric mucous membrane in 7 of 8 subjects.

The individual findings (and the summary findings) are set out in Tables 4 to 7.

Evaluation of the visual findings and of the photographic documentation allows the summary assessment to be made that dimethylpolysiloxane chewable tablets and dimethylpolysiloxane are able to form an adhesive film on the gastric mucous membrane and in the proximal part of the duodenum.

                  TABLE 1                                                          ______________________________________                                         Anamnestic data on the subjects in the dimethyl-                               polysiloxane study                                                                     Mean  SD       Min    Max  Median                                      ______________________________________                                         Age       32.15   4.51     25   40   31.5 years                                Height    179.75  7.31     170  191  181 cm                                    Weight    78      7.68     63   90   77 kg                                     Systol. blood                                                                            116     9.99     101  130  114.5 mmHg                                pressure                                                                       Diast. blood                                                                             78.62   8.44     62   90   81 mmHg                                   pressure                                                                       Pulse     63.5    10.94    53   88   60.5/min                                  ______________________________________                                    

                  TABLE 8                                                          ______________________________________                                         40 mg dimethylpolysiloxane chewable tablets                                    Composition per tablet:                                                        ______________________________________                                         I.   (1)    Dimethylpolysiloxane DAB9                                                                             40.000 mg                                        (2)    Highly disperse silica DAB9                                                                           12.555 mg                                        (3)    Peppermint oil DAB9    0.300 mg                                                Aniseed oil DAB9       0.033 mg                                         (4)    Microcrystalline cellulose DAB9                                                                       200.000 mg                                  II.  (5)    Mannitol DAB9          338.111 mg                                       (6)    Saccharin sodium DAB9  0.667 mg                                         (7)    Carboxymethylcellulose sodium DAB9                                                                    1.667 mg                                    III. (9)    Magnesium stearate DAB9                                                                               3.333 mg                                         (10)   Maize starch DAB9      3.333 mg                                    ______________________________________                                    

DAB9 is the abbreviation for Deutches Arznei Buc (German Pharmaceutical Handbook) 9th Edition.

                  TABLE 2                                                          ______________________________________                                         Change in the pH values in the stomach on medica-                              tion with dimethylpolysiloxane                                                 Sub;. No.                                                                      1         2      3      4     5    6    7    8                                 ______________________________________                                         Before 1.80   1.96   1.92 1.98  1.51 2.11 6.03 1.69                            med.                                                                           30 min 2.06   --     --   --    --   --   --   --                              after                                                                          med.                                                                           2 hours                                                                               2.15   2.04   4.48 7.49  3.84 2.32 6.83 2.67                            after                                                                          med.                                                                           No. of 2      4      4    2     2    2    4    2                               Tab.                                                                           ______________________________________                                    

A positive influence on the pH by the medication is confirmed by the sign test (p<0.05, two-sided). However, no influence of the number of tablets on the increase in the pH can be established.

Subject 7 has a deformed duodenal cap due to scarring, without stenosis, was not included in h calculation because of the high pH values.

                  TABLE 3                                                          ______________________________________                                         Positive reaction on administration of dimethyl-                               polysiloxane chewable tablets                                                  ______________________________________                                         2 dimethylpolysiloxane tablets                                                 Subjects with                                                                  positive reaction* no reaction                                                                              n                                                 ______________________________________                                         8                  0         8                                                 ______________________________________                                          *The reaction was minimal milky secretion in 5 of 8 subjects             

    4 dimethylpolysiloxane tablets                                                 Subjects with                                                                  positive reaction**                                                                               no reaction                                                                              n                                                 ______________________________________                                         8                  0         8                                                 ______________________________________                                          **The reaction was minimal milky secretion in 1 of 8 subjects, otherwise       always a relatively large amount of milky secretion                      

                  TABLE 4                                                          ______________________________________                                         Findings at the first investigation                                                         No. of                                                                   Time* tabl.    Finding                                                  ______________________________________                                         Subject No. 1                                                                           1       4        Signs of antral gastritis.                                                     Otherwise duodenum, stomach                                                    and oesophagus macroscopic-                                                    ally normal.                                         Subject No. 1                                                                           2       4        Gastric juice in the fundus;                                                   milky, cloudy and floc-                                                        culent.                                              Subject No. 1                                                                           3       4        Only minimal residues in the                                                   fundus. Otherwise empty as                                                     far as the deep duodenum.                            Subject No. 2                                                                           1       2        Signs of slight antral                                                         gastritis.                                                                     Otherwise duodenum, stomach                                                    and oesophagus macroscopic-                                                    ally normal.                                         Subject No. 2                                                                           2       2        Gastric juice in the fundus;                                                   milky, cloudy and flocculent                         Subject No. 2                                                                           3       2        Still milky substance in the                                                   fundus. Duodenum and antrum                                                    empty.                                               Subject No. 3                                                                           1       2        Small hiatus hernia with                                                       reflux of grade 0-1.                                                           Otherwise duodenum, stomach                                                    and oesophagus macroscopic-                                                    ally normal.                                         Subject No. 3                                                                           2       2        Gastric juice in the fundus;                                                   milky, cloudy and flocculent                         Subject No. 3                                                                           3       2        Minute residues of milky,                                                      flocculent deposits.                                                           Fundus with a film-like                                                        coating over large areas.                                                      Duodenum empty.                                      Subject No. 4                                                                           1       4        Duodenum, stomach and                                                          oesophagus macroscopically                                                     normal.                                              Subject No. 4                                                                           2       4        Gastric juice in the fundus;                                                   milky, cloudy and flocculent                         Subject No. 4                                                                           3       4        Slightly cloudy, milky                                                         gastric juice. Otherwise                                                       duodenum, stomach, oesopha-                                                    gus normal.                                          Subject No. 5                                                                           1       4        Small hiatus hernia with                                                       reflux oesophagitis (grade                                                     0-I).                                                                          Otherwise duodenum, stomach                                                    and oesophagus macroscopic-                                                    ally normal.                                         Subject No. 5                                                                           2       4        Antrum with scabby-milky                                                       coating in the fundus. Very                                                    cloudy, milky fluid.                                 Subject No. 5                                                                           3       4        Residues of milky flakes in                                                    the fundus.                                                                    A few plaques in the antrum.                                                   Duodenum empty.                                      Subject No. 6                                                                           1       4        Duodenum, stomach and                                                          oesophagus normal.                                   Subject No. 6                                                                           2       4        A few whitish, milky spots                                                     in the antrum. Otherwise                                                       cloudy, milky coating in the                                                   fundus.                                              Subject No. 6                                                                           3       4        Very cloudy, milky fluid                                                       deposited on the fundus.                                                       A few plaques in the antrum.                                                   Duodenum empty.                                      Subject No. 7                                                                           1       2        Deformed duodenal cap due to                                                   scarring, without stenosis.                                                    Stomach and oesophagus                                                         normal.                                              Subject No. 7                                                                           2       2        Low-viscosity, milky depo-                                                     sits in the fundus. Antrum,                                                    duodenum empty.                                      Subject No. 7                                                                           3       2        Minimal spots of milky                                                         deposits in the stomach                                                        fundus.                                                                        Otherwise duodenum and                                                         antrum empty.                                        Subject No. 8                                                                           1       2        Duodenum, stomach and                                                          oesophagus normal.                                   Subject No. 8                                                                           2       2        Low-viscosity but cloudy,                                                      milky secretion in the                                                         fundus, film-like coating.                                                     Antrum, duodenum empty.                              Subject No. 8                                                                           3       2        Low-viscosity milky secre-                                                     tion as film-like coating.                                                     Secretion cloudy.                                                              Antrum, duodenum empty.                              ______________________________________                                          *Time 1 = immediately before medication                                        Time 2 = 1/2 hour after medication                                             Time 3 = 2 hours after medication                                        

                  TABLE 5                                                          ______________________________________                                         Findings at the second investigation                                           (after 7 days)                                                                              No. of                                                                   Time* Tabl.    Finding                                                  ______________________________________                                         Subject No. 1                                                                           1       2        Duodenum, stomach, oesopha-                                                    gus normal, distinct macro-                                                    scopic improvement in antral                                                   gastritis.                                                                     pH 1.80                                              Subject No. 1                                                                           2       2        Distinctly less milky                                                          secretion and film coating.                                                    Otherwise finding unchanged.                                                   pH 2.06                                              Subject No. 1                                                                           3       2        Minimal milky secretion in                                                     the fundus.                                                                    Duodenum, stomach normal.                                                      pH 2.15                                              Subject No. 2                                                                           1       4        Continuing signs of slight                                                     antral gastritis. Otherwise                                                    duodenum, stomach and                                                          oesophagus normal.                                                             pH 1.96                                              Subject No. 2                                                                           2       4        Large amount of high-viscos-                                                   ity milky, secretion in the                                                    fundus. Otherwise antrum                                                       empty.                                               Subject No. 2                                                                           3       4        Large amount of high-viscos-                                                   ity milky secretion in the                                                     fundus. Antrum, duodenum                                                       empty.                                                                         pH 2.04                                              Subject No. 3                                                                           1       4        Small hiatus hernia with                                                       reflux of grade 0-1.                                                           Otherwise duodenum, stomach                                                    and oesophagus macroscopic-                                                    ally normal.                                                                   pH 1.92                                              Subject No. 3                                                                           2       4        Large amount of high-viscos-                                                   ity milky secretion in the                                                     antrum and fundus, duodenum                                                    empty.                                               Subject No. 3                                                                           3       4        Large amount of residues of                                                    milky coating and secretion                                                    in the antrum and fundus.                                                      Duodenum empty.                                                                pH 4.48                                              Subject No. 4                                                                           1       2        Duodenum, stomach and                                                          oesophagus macroscopically                                                     normal.                                                                        pH 1.98                                              Subject No. 4                                                                           2       2        Minimal milky secretion in                                                     the fundus. Duodenum, antrum                                                   empty.                                               Subject No. 4                                                                           3       2        Only residues of cloudy,                                                       milky secretion in fundus.                                                     Duodenum and antrum other-                                                     wise empty.                                                                    pH 7.49                                              Subject No. 5                                                                           1       2        Small hiatus hernia with                                                       reflux oesophagitis (grade                                                     0-1).                                                                          pH 1.51                                              Subject No. 5                                                                           2       2        Minimal milky secretion in                                                     the corpus and in the                                                          antrum. Duodenum empty.                              Subject No. 5                                                                           3       2        Little cloudy secretion in                                                     the fundus. Antrum, duodenum                                                   empty.                                                                         pH 3.84                                              Subject No. 6                                                                           1       2        Duodenum, stomach and                                                          oesophagus normal.                                                             pH 2.11                                              Subject No. 6                                                                           2       2        Little milky, cloudy secre-                                                    tion in the fundus and                                                         corpus.                                              Subject No. 6                                                                           3       2        Minimal secretion in the                                                       duodenum and in the stomach.                                                   pH 2.32                                              Subject No. 7                                                                           1       4        Deformed duodenal cap due to                                                   scarring, without stenosis.                                                    Stomach and oesophagus                                                         normal.                                                                        pH 6.03                                              Subject No. 7                                                                           2       4        Little milky cloudy secre-                                                     tion in the fundus.                                                            Antrum duodenum empty.                               Subject No. 7                                                                           3       4        Minimal secretion in the                                                       fundus without the milky                                                       cloudiness.                                                                    Duodenum, antrum empty.                                                        pH 6.83                                              Subject No. 8                                                                           1       4        Duodenum, stomach and                                                          oesophagus normal.                                                             pH 1.69                                              Subject No. 8                                                                           2       4        Minimal, milky secretion as                                                    film-like coating.                                                             Tablets unchewed in the                                                        corpus.                                                                        Duodenum empty.                                      Subject No. 8                                                                           3       4        Now large amount of cloudy,                                                    milky secretion as film-like                                                   coating in the fundus.                                                         Corpus, duodenum, antrum                                                       empty.                                                                         pH 2.67                                              ______________________________________                                          *Time 1 = immediately before medication                                        Time 2 = 1/2 hour after medication                                             Time 3 = 2 hours after medication                                        

                  TABLE 6                                                          ______________________________________                                         Summary of the findings in the dimethylpolysiloxane                            study                                                                                               Frequency of                                                             No. of                                                                               occurrence                                                               subj. 2T    4T    t2  t3  t 2 + 3                               ______________________________________                                         Signs of antral gastritis                                                                       2                                                             Antral gastritis macroscop.                                                                     1                                                             improved                                                                       Duodenum and antrum empty                                                                       6       6     4       4   6                                   Duodenum empty   3             3   1   2                                       Corpus empty     1             1       1                                       Minimal/little milky                                                                            6       5     1   2   2   2                                   secretion                                                                      Minimal/residues of spots                                                                       4       2     2   1   3                                       of milky deposits                                                              A few plaques in the antrum                                                                     2       0     2   0   2                                       Milky, cloudy, flocculent                                                                       4       2     2   2       2                                   gastric juice                                                                  Milky deposits   5       3     2   2   1   2                                   Large amount of high-                                                                           3       0     3   1   1   1                                   viscosity milky secretion                                                      Large amount of residues                                                                        1       0     1       1                                       of milky coating and                                                           secretion                                                                      ______________________________________                                          Abbreviations:                                                                 No. of subj. = number of subjects;                                             T = tablets;                                                                   t = time                                                                 

                  TABLE 7                                                          ______________________________________                                         Findings in the dimethylpolysiloxane study                                                                          Invest-                                                  Subj.         No. of  igation                                                  No.  Date     tabl.   time                                      ______________________________________                                         Signs of antral gastritis                                                                       1      March 15       1                                       Antral gastritis macroscop.                                                                     1      22.3.          1                                       improved                                                                       Signs of antral gastritis                                                                       2      March 15       1                                                        2      22.3.          1                                       Small hiatus hernia                                                                             3      March 15       1                                                        3      22.3.          1                                                        5      March 15       1                                                        5      22.3.          1                                       Deformed duodenal cap                                                                           7      March 15       1                                       due to scarring, 7      22.3.          1                                       without stenosis.                                                              Duodenum and antrum empty                                                                       2      March 15 2     3                                                        3      March 15 2     3                                                        4      22.3.    2     2 and 3                                                  5      22.3.    2     2 and 3                                                  7      March 15 2     2 and 3                                                  8      March 15 2     2 and 3                                                  2      22.3     4     2 and 3                                                  4      March 15 4     3                                                        7      22.3.    4     2 and 3                                                  8      22.3.    4     3                                       Duodenum empty   5      March 15 4     3                                                        6      March 15 4     3                                                        8      22.3.    4     2                                       Corpus empty     8      22.3.    4     3                                       Minimal milky secretion                                                                         8      22.3.    4     2                                       (tablets unchewed in the                                                       corpus)                                                                        Minimal milky secretion in                                                                      1      22.3.    2     2 and 3                                 the fundus       4      22.3.    2     2 and 3                                                  5      22.3.    2     3                                                        6      22.3.    2     2                                       Minimal milky secretion in                                                                      5      22.3.    2     2                                       the corpus and antrum                                                                           6      22.3.    2     2                                       Fundus with minimal spots                                                                       7      March 15 2     3                                       of milky deposits                                                                               1      March 15 4     3                                       Little milky secretion in                                                                       7      22.3.    4     2                                       the fundus                                                                     Stomach with minimal spots                                                                      7      March 15 2     3                                       of milky deposits                                                              Minimal secretion in the                                                                        6      22.3.    2     3                                       duodenum and antrum                                                            Minimal secretion in the                                                                        7      22.3.    4     3                                       fundus without milky                                                           cloudiness                                                                     A few whitish spots in                                                                          6      March 15 4     2                                       the antrum                                                                     Minute residues of milky,                                                                       3      March 15 2     3                                       flocculent deposits                                                            Residues of milky flakes                                                                        5      March 15 4     3                                       in the fundus                                                                  A few plaques in the                                                                            5      March 15 4     3                                       antrum           6      March 15 4     3                                       Milky, cloudy, flocculent                                                                       2      March 15 2     2 and 3                                 gastric juice in the fundus                                                                     3      March 15 2     2                                                        1      March 15 4     2                                                        4      March 15 4     2 and 3                                 Low-viscosity, milky                                                                            7      March 15 2     2                                       deposits in the fundus                                                                          8      March 15 2     2 and 3                                 Fundus with film-like                                                                           3      March 15 2     3                                       coating over large area                                                        Antrum and fundus with                                                                          5      March 15 4     2                                       scabby-milky coating                                                           Fundus with cloudy, milky                                                                       6      March 15 4     2 and 3                                 coating                                                                        Large amount of high-                                                                           2      22.3.    4     2 and 3                                 viscosity milky secretion                                                                       3      22.3.    4     2                                       in the fundus                                                                  Large amount of high-                                                                           3      22.3.    4     2                                       viscosity milky secretion                                                      in the antrum                                                                  Large amount of cloudy,                                                                         8      22.3.    4     3                                       milky secretion as film-like                                                   coating in the fundus                                                          Large amount of residues of                                                                     3      22.3.    4     3                                       milky coating and secretion                                                    in the fundus.                                                                 Large amount of residues of                                                                     3      22.3.    4     3                                       milky coating and secretion                                                    in the antrum                                                                  ______________________________________                                    

Dimethylpolysiloxane is obtained by hydrolysis and polycondensation of dichlorodimethylsilane and chlorotrimethylsilane. The various types differ in the nominal viscosity which is expressed by the number with the substance name.

The degree of polymerization (n=20 to 400) is such that the kinematic viscosity ranges from 20 to 1,000 mm² ·s⁻¹ (20 to 1,000 cSt).

The structural formula of dimethylpolysiloxane is: ##STR1##

S 184 silicone antifoam agent from Wacker Chemie was used to prepare the chewable tablets in the tests described hereinbefore. Equivalent results are also achieved with dimethylpolysiloxane or silicone oils with a kinematic viscosity in the range from 100 to 10,000 mm² ·s⁻¹, in particular 300 to 3,000 mm² ·s⁻¹.

Aerosil 2000 was employed as highly dispersed silica. 

We claim:
 1. A method of treating a gastric or duodenal ulcer in a patient in need of such treatment, which comprises orally administering to the patient a composition consisting essentially of an ulcer-treating effective amount of dimethylpolysiloxane.
 2. A method according to claim 1 wherein the dimethylpolysiloxane has a kinematic viscosity in the range of 100 to 10,000 mm² ·s⁻¹.
 3. A method according to claim 1 wherein the composition contains silica gel. 